Chronic sinusitis is a prominent feature of the genetic disorder cystic fibrosis (CF). Abnormal function of the CF Transmembrane Conductance Regulator (CFTR) causes CF and investigation of this protein has significantly increased our understanding of the basic defect in this disorder. CFTR functions as a cAMP-activated chloride channel and appears to regulate the function of another chloride channel in respiratory epithelia. It is expressed in the pulmonary airways including the epithelia lining the nasal sinuses. These observations indicate that CFTR plays an important role in electrolyte movement and mucociliary transport in nasal respiratory epithelium. It is therefore plausible that certain alterations of CFTR function may occur that modify epithelial cell function predisposing individuals to the development of chronic sinusitis. We will test the hypothesis that variations in the CFTR gene occur in some patients with chronic sinusitis in the absence of the diagnosis of CF by pursuing the following aims: (1) To determine whether patients with chronic sinusitis have a higher frequency of CF mutations than the general population. One hundred individuals with chronic sinusitis collected by the Clinical Core and any patients who have evidence of a normal epithelial electrolyte transport will be screened for 6 mutations common in CF and 10 mutations that have been found in patients with unusual forms of cystic fibrosis that retain the feature of chronic sinusitis. (2) To collect families in which 2 or more members have chronic sinusitis and determine whether the affected individuals carry the same CFTR genes by performing linkage studies using highly polymorphic DNA markers with the CFTR gene. (3) To search for deleterious mutations in the CFTR genes from chronic sinusitis patients carrying one known CF mutation (identified in Aim 1) and patients demonstrating linkage with CFTR gene (identified in Aim 2). A rapid mutation detection method called denaturing gradient gel electrophoresis will be used to examine the entire coding region of each CFTR gene. (4) To determine the chloride transport properties of CFTR protein bearing mutations found in patients with chronic sinusitis. Mutant CFTR cDNA will be expressed airway epithelial cells using a rous sarcoma virus and an adeno-associated virus expression system. CFTR function will assessed by chloride efflux and patch-clamp studies.